The Role of SNCG in the Carcinogenesis of Uterine Papillary Serous Carcinoma

描述（由申请人提供）：子宫内膜癌是最常见的妇科恶性肿瘤，预计2008年美国将有40,100例新发病例。子宫乳头状浆液性癌（UPSC）是一种侵袭性的组织学亚型，约占所有病例的10%，但几乎占子宫内膜癌死亡的40%。与更常见的子宫内膜样癌不同，UPSC的发病机制在很大程度上尚不清楚。这些癌症通常出现在晚期，对化疗的反应很差。缺乏有效和有针对性的治疗策略。我们进行了一个聚焦的，真实的时间PCR阵列比较类胶质瘤（石川）和UPSC（SPEC 2）细胞系，揭示了最高表达的基因在SPEC 2超过石川是促转移癌基因突触核蛋白-3（SNCG）。我们还发现SNCG mRNA和蛋白在SPEC 2和类子宫内膜癌细胞系中高度表达。免疫组化染色结果显示，两组间表达相似。最后，SNCG沉默的shRNA导致显着减少在SPEC 2细胞的细胞增殖和增加的SPEC 2细胞对紫杉醇诱导的凋亡的敏感性。SNCG在乳腺癌中得到了很好的研究，它与晚期和侵袭性疾病以及对微管破坏剂的耐药性相关。在这项研究中，我们将在一系列的300 UPSC肿瘤和血清标本与临床和病理预后因素，化疗反应，结果UPSC患者的SNCG表达。由于SNCG首次在乳腺癌中被描述，并且乳腺癌和UPSC之间的联系一直被怀疑，我们还将研究有乳腺癌个人史的UPSC患者中SNCG的表达。然后，我们将研究SNCG影响UPSC肿瘤细胞增殖、侵袭和对抗微管药物敏感性的分子机制，方法是使用各种方法抑制SPEC 2细胞系中的SNCG，并将结果与另外两种UPSC细胞系以及过表达SNCG的tet诱导型石川细胞系进行比较。我们还将研究其他化疗药物和靶向药物对细胞系的差异作用。总之，我们假设SNCG在UPSC中的表达与其侵袭性肿瘤表型、不良预后和化疗耐药性相关，并且其表达的抑制降低了肿瘤的侵袭和转移潜力，并提高了其对微管靶向化疗的敏感性。SNCG可能是UPSC中与晚期疾病、无进展生存率降低和对标准化疗反应降低相关的新的预后生物标志物。此外，SNCG可被开发为一种新的治疗靶点。它在UPSC中的表达可用于帮助指导我们选择最有效的化疗方案。公共卫生相关性：通过研究SNCG在UPSC中的作用机制，我们希望为UPSC的新治疗方法奠定基础，这种方法最终可能与我们目前治疗所有子宫内膜癌的方法不同。我们相信SNCG有潜力作为UPSC中攻击行为的生物标志物，并可能有助于指导用于治疗它的抗肿瘤药物的选择。此外，我们将试图表明SNCG表达可能将UPSC和乳腺癌联系起来，这将对两个患者人群的筛查和预防性手术产生影响。

DESCRIPTION (provided by applicant): Endometrial cancer is the most common gynecologic malignancy with an estimated 40,100 new cases expected in the United States in 2008. Uterine papillary serous carcinoma (UPSC) is an aggressive histologic subtype accounting for about 10% of all cases but almost 40% of endometrial cancer deaths. Unlike for the more common endometrioid endometrial carcinomas, the pathogenesis of UPSC is largely unknown. These cancers often present in advanced stages and exhibit poor response to chemotherapy. Effective and tailored treatment strategies are lacking. We performed a focused, real time PCR array comparing an endometrioid (Ishikawa) and a UPSC (SPEC2) cell line which revealed that the most highly expressed gene in SPEC2 over Ishikawa was the pro-metastatic oncogene synuclein-3 (SNCG). We also showed that SNCG mRNA and protein were highly expressed in SPEC2 versus endometrioid endometrial cancer cell lines. Similar expression data was obtained by Immunohistochemical staining. Finally, silencing of SNCG by shRNA caused a significant decrease in cell proliferation in SPEC2 cells and increased sensitivity of SPEC2 cells to paclitaxel induced apoptosis. SNCG is well studied in breast cancer where it correlates with advanced stage and aggressive disease as well as resistance to microtubule-disrupting agents. In this study, we will correlate SNCG expression in a series of 300 UPSC tumors and serum specimens with clinical and pathologic prognostic factors, response to chemotherapy, and outcomes in UPSC patients. Since SNCG was first described in breast cancer and a link between breast cancer and UPSC has long been suspected, we will also investigate SNCG expression in UPSC patients with a personal history of breast cancer. We will then study the molecular mechanisms by which SNCG influences proliferation, invasion, and sensitivity to antimicrotubule drugs in UPSC tumor cells by using various methods to inhibit SNCG in the SPEC2 cell line and compare results to two additional UPSC cell lines as well as a tet-inducible Ishikawa cell line overexpressing SNCG. We will also investigate the differential effect of other chemotherapeutics and targeted agents on the cell lines. In summary, we hypothesize that SNCG expression in UPSC is associated with its aggressive tumor phenotype, poor prognosis, and chemoresistance and that inhibition of its expression decreases the invasive and metastatic potential of the tumor and improves its sensitivity to microtubule targeting chemotherapy. SNCG may be a novel prognostic biomarker in UPSC correlating with advanced disease, decreased progression-free survival, and decreased response to standard chemotherapy. Additionally, SNCG could be developed as a novel therapeutic target. Its expression in UPSC could be used to hel guide our decision making in choosing the most effective chemotherapy. PUBLIC HEALTH RELEVANCE: By investigating the mechanism of action of SNCG in UPSC, we hope to lay the groundwork for a new therapeutic approach to UPSC that may ultimately have to be different than our current approach to treating all endometrial cancers. We believe that SNCG has potential as a biomarker for aggressive behavior in UPSC and may be able to help direct the choices of antineoplastic agents used to treat it. In addition, we will attempt to show that SNCG expression may link UPSC and breast cancer which would have implications regarding screening and prophylactic surgery in the two patient populations.